1. The Field of the Invention
The present invention is related to methods and compositions for use in systemically delivering potent pharmacological agents having cardiovascular activities to patients in a dose-to-effect manner. More particularly, the present invention is directed to methods and compositions for noninvasive administration of precise doses of potent pharmacological agents having cardiovascular functions (such as vasodilating, calcium channel blocking, beta-blocking, seritonin receptor blocking, angina blocking, anti-hypertensive, and cardiac stimulating properties) and renal vascular functions (such as increasing urine output).
2. The Prior Art
The proper functioning of a person's cardiovascular system determines to a large extent the quality of life that person will enjoy. There have been significant advances in recent years in understanding the complex mechanisms which control the cardiovascular system. This had led to the development of a host of potent new drugs available for clinical use in treating cardiovascular conditions such as congestive heart failure, hypertension, angina, ventricular and atrial fibrillation, and related conditions, and current expectations are that additional potent drugs will continue to become available in the future.
For example, the physician has at his disposal a vast array of hypotensive drugs useful for treating high blood pressure. Blood pressure ("BP") is the product of two hemodynamic factors, cardiac output ("CO") and total peripheral resistance ("TPR"): EQU BP=CO.times.TPR
A reduction in blood pressure can occur only with a reduction in either CO or TPR, or both.
It is believed that beta-blockers, such as esmolol, nadolol, pindolol, and timolol, reduce blood pressure by decreasing the heat rate or cardiac output. Some beta-blockers, such as atenolol and metoprolol, are known as cardioselective beta-blockers because they have a greater affinity for the beta.sub.1 adrenoceptors that predominate in the heart than for the beta.sub.2 receptors that predominate in the bronchi and peripheral vasculature. The cardioselective nature of these beta-blockers is lost if too great a dose is administered.
All beta-blockers, however, if administered in excess, may result in impaired pulmonary function, wheezing, and asthmatic attacks. In addition, there may be serious adverse cardiovascular effects from the use of beta-blockers, such as bradycardia (abnormally slow heart rate), profound hypotension, and even precipitation of severe congestive heart failure. Adverse central nervous system ("CNS") effects of beta-blockers include dizziness, fatigue, mental depression, and in some cases hallucinations; short-term memory impairment and vertigo have also been observed. There may also be adverse gastrointestinal ("GI") reactions, such as diarrhea and nausea.
As a result, it will be appreciated that while beta-blockers have a very valuable place in cardiac treatment, it is critical that the appropriate dosage be given to a patient in order to avoid the dangers and problems caused by overdosing or underdosing.
Other hypotensive drugs, such as nitroprusside and hydralazine, reduce blood pressure by lowering the total peripheral resistance by direct vasodilation. These drugs are particularly potent and are usually given in an emergency or when other hypotensive treatments have failed. Even slight overdoses of this type of hypotensive drug may result in headache, tachycardia, nausea, and diarrhea, and may even precipitate angina pectoris or ventricular arrhythmia.
Still other hypotensive drugs, such as prazosin, are alpha.sub.1 -blockers which are also capable of reducing blood pressure by lowering the total peripheral resistance as a result of vasodilating effects. An overdose of prazosin may result in headache, drowsiness, palpitation, nausea, and even fainting.
Labetolol is a unique hypotensive drug which combines the features of alpha-blockers with beta-blockers. Blood pressure is reduced due to a decrease in systemic vascular resistance, but usually without a substantial reduction or increase in heart rate, cardiac output, or stroke volume. Unfortunately, labetolol shares the toxic potentials of both the beat and the alpha-blocking agents. In particular, labetolol overdose may promote or exacerbate congestive heart failure, bronchospasm, hypotension, and bradycardia.
Other hypotensive drugs, such as methyldopa and clonidine, inhibit sympathetic vasomotor centers thereby reducing peripheral sympathetic nervous system activity, blood pressure, and heart rate with little change in total peripheral resistance. An overdose of these drugs may result in drowsiness, headache, nausea, dry mouth, palpitation and tachycardia, bradycardia, congestive heart failure, rash, impotence, hepatic abnormalities, and muscle cramps.
Some hypotensive drugs, such as captopril and enalapril, reduce blood pressure by suppressing the renin-angiotensin-aldosterone ("RAA") system. These drugs inhibit the angiotensin-converting enzyme ("ACE") thereby resulting in arterial and possibly venous dilation. Thus, blood pressure is reduced by decreasing the total peripheral resistance with either no change or an increase in heart rate, stroke volume, or cardiac output.
These ACE-inhibiting drugs, if administered in excess, may also result in neutropenia, an abnormally low white blood cell count, which may further lead to systemic or regional infections and possible death. Other adverse effects from overdosing of ACE inhibitors include proteinuria (an abnormally high amount of protein in the urine), rash, taste impairment, excessive hypotension, tachycardia, angina, palpitations, and even myocardial infarction and congestive heart failure.
The physician also has at his disposal a large number of vasodilating drugs useful for treating angina, congestive heart failure, vasospasm, and in some cases hypertension. However, each of these vasodilating drugs also has serious side effects which present dangers when the proper dose for the patient is not given.
For instance, calcium channel blockers (such as diltiazem, nifedipine, and verpamil) dilate the coronary and systemic arteries. This is accomplished by inhibiting the transmembrane influx of extracellular calcium ions across the membranes of the myocardial cells and vascular smooth muscle cells. Calcium plays important roles in the excitation-contraction coupling process of the heart and the vascular smooth muscle cells and in the electrical discharge of the specialized conduction cells of the heart.
Nevertheless, despite their advantages, an overdose of a calcium channel blocker may lead to bradycardia, asymptomatic asystole, hypotension, congestive heart failure, anorexia, nausea, and hallucinations.
Other vasodilating drugs include the organic nitrates, such as isosorbide and nitroglycerin. The drug nitroglycerin, as applied to the present invention, is specifically treated a copending continuation-in-part application Ser. No. 07/058,898, filed June 05, 1987, in the names of the inventors hereof, and entitled "Methods and Compositions for Noninvasive Dose-to-Effect Administration of Nitroglycerin," which application is incorporated herein by specific reference.
Organic nitrates relax vascular smooth muscles. They are particularly useful for relief of angina pectoris, for prophylactic management of situations likely to provoke angina attacks and for long-term prophylactic management of angina pectoris. Isosorbide may be administered sublingually, lingually, buccally, nasally, or orally. However, an overdose of isosorbide may result in headache, dizziness, nausea, tachycardia, hypotension, fainting, or other dangerous depressions of vital body functions.
Finally, the physician has at his disposal a number of cardiac drugs useful for treating ventricular fibrillation, acute ventricular arrhythmias, and congestive heart failure. Again, these drugs, while useful, can be very dangerous when the patient's susceptibility to the drug makes it difficult to know the proper dose.
Amrinone, for example, is an inotropic drug which increases the force and velocity of myocardial systolic contraction. In addition, amrinone has vasodilatory activity affecting vascular smooth muscle. In patients with congestive heart failure, amrinone produces substantial increases in cardiac output.
However, serious adverse effects may arise in the event of an overdose of amrinone; these adverse effects include: thrombocytopenia (an abnormal decrease in the number of blood platelets), arrhythmias, hypotension, nausea, vomitting, diarrhea, hepatotixicity marked by abnormal liver function, and hypersensitivity.
Bretylium and lidocaine are well-known anti-arrhythmic drugs. Bretylium is used in the prophylaxis and treatment of ventricular fibrillation. However, because it commonly causes hypotension, and may increase ventricular irritability, bretylium is considered a second choice drug. Lidocaine is a CNS-depressing drug which controls ventricular arrhythmias. It also produces sedative, analgesic, and anti-convulsant effects. Overdoses may result in seizures, respiratory arrest, dizziness, nausea, unconsciousness, or even coma.
In addition to drugs for treating cardiovascular conditions, many new drugs for treatment of renal vascular functions have been developed in recent years. However, like most drugs affecting the cardiovascular system, the drugs affecting the renal vascular system must be precisely administered to avoid serious side effects or the dangers of overdosing and underdosing.
Dopamine is a very useful drug for increasing renal blood flow and urine output. Its application is most beneficial in a patient who has a Foley catheter in his uninary bladder. In its clinical application, dopamine is administered until urine output is significantly increased or approaches a normal range.
Despite its benefits, the detriment of using too much dopamine is reflected in increases in the heart rate, blood pressure, cardiac output, and myocardial oxygen consumption. These effects are extremely dangerous in patients with ischemic cardiac disease. Hence, precise dosage control is critical to the effective use of dopamine.
Despite the tremendous advances in the field of pharmacology, physicians continue to administer these new cardiovascular and renal vascular drugs using substantially the same techniques that have been employed for many decades.
Thus, almost all cardiovascularly and renal vascularly active pharmacological drugs continue to be administered via two routes, the oral dosage form for absorption through the stomach and/or intestines or by intramuscular or intravenous injection. These two drug administration modalities are the most frequently used despite the fact that both of these routes suffer from significant disadvantages in particular situations.
The simplest and most prevalent administration route is the oral dosage form. To use this method, a pharmacological drug is incorporated into a tablet, a capsule, or into a liquid base. The patient then ingests the predetermined dose of the drug. Oral administration of a drug is extremely convenient, and, for many drugs, it will continue to be the method of choice. Such administration is nonthreatening and is painless to the patient. For most patients, it is also very simple.
Nevertheless, oral administration of a drug suffers from the disadvantage that many patients, particularly geriatric patients, frequently have difficulty swallowing pills. Such patients often refuse to cooperate in swallowing a liquid medication. Even more importantly, absorption of a drug into the bloodstream after swallowing a tablet varies from patient to patient and in the same patient from time to time. The absorption of the drug is dependent upon the movement of the drug from the stomach to the small and large intestines and the effect of secretions from these organs.
Even more important, there is typically a substantial delay between the time of oral administration of a drug and the time that the drug begins to have the desired therapeutic effect on the patient's cardiovascular, renal vascular, or other systems. Generally, a drug must pass from the stomach into the small and large intestines before it will be absorbed into the patient's bloodstream; unfortunately, this typically takes forty-five minutes or longer. For many clinical situations, such a delay is unacceptable.
Further, many drugs taken orally, particularly cardiovascular-acting drugs, are metabolized almost immediately--they are removed from or rendered ineffective by the patient's system before they can have any therapeutic effect. This occurs because the veins from the small and large intestines, and to a certain extent also the stomach, drain into the liver. Thus, drugs entering the patient's, bloodstream through the intestines immediately pass through the patient's liver before distribution throughout the remainder of the patient's body.
Unfortunately, upwards of sixty percent of a drug (and essentially one hundred percent of certain drugs) may be removed from the patient's bloodstream during this "first pass" through the liver. The result is that the oral route of administration is impractical for many drugs, particularly many cardiovascular-acting and renal vascular-acting drugs.
Further, additional stress is placed on the liver as it removes the excess drug from the bloodstream. This is particularly severe if the cardiovascular or renal vascular treatment has been occurring over an extended period of time. The liver may become overloaded with the drug's metabolite which then must be excreted in the patient's urine. As a result, there is an increased risk of hepatic or renal disorders.
Yet a further difficulty encountered when administering cardiac and related drugs orally is that dosages are prepared or determined for use with an "average" patient. This is entirely acceptable for many drugs, but some drugs, such as those that have a cardiovascular, anti-hypertensive, vasodilating, anti-anginal, or renal vascular effect, have a widely varying effect on different patients, depending upon individual variations in susceptibility to the particular drug utilized.
Underdosing a patient because of a low susceptibility to the drug fails to evoke the cardiovascular or renal vascular response sought by the physician. Overdosing the patient can result in too much vasodilation, hypotension, cardiac or respiratory depression, other side effects such as headaches, nausea, or other dangerous depression of vital body functions.
Moreover, the slow and uncertain response time for the onset of an observable reaction to a cardiovascular drug when taken orally makes it even more difficult to determine a proper dose for a particular patient; the physician may not learn for an hour, or with some drugs for a few days, whether the patient was underdosed or overdosed. By then, extraordinary measures may be necessary to remedy the patient's condition.
In order to avoid these serious disadvantages inherent in the oral administration route, physicians frequently resort to the injection route for administering many drugs. Injecting a drug (generally intravenously or intramuscularly) results in rapid entry of the drug into the patient's bloodstream and onset of the desired effect. In addition, this type of delivery avoids the removal of large quantities of the drug by the patient's liver that accompanies oral administration. Rather, the drug becomes rapidly distributed to various portions of the patient's body before exposure to the liver; thus, the drug is removed by the liver only after it has first reached the cardiovascular or renal vascular systems.
Most patients have at least some aversion to receiving injections. In some patients, this aversion may be so pronounced as to make the use of injections of serious concern to the physician. Since intense psychological stress can exacerbate a patient's debilitated condition, it sometimes becomes undesirable to use injections where the patient is seriously ill, suffers from a debilitating condition or injury, or where there is no immediate medical assistance.
To compound the problem facing a physician, the individual variation in susceptibility and metabolism with respect to cardiovascular drugs, which makes it difficult to select an appropriate dose for oral administration is even more profound when utilizing the injection route. This is because smaller doses have an increased effect due to the rapidity in which the drug enters the bloodstream because large portions of the drug are not immediately metabolized by the liver.
In order to prevent overdosing a patient with potent cardiovascular drugs, a prudent physician typically injects a patient with a lower than average dose, and later supplements the dose with additional injections as they appear necessary. This, of course, makes necessary the use of repeated injections, which in turn greatly increases the stress on the patient. It is no uncommon for a patient to come to feat that it is time for yet another injection every time the patient sees a member of the hospital staff, which is often the case for those most in need of potent drugs.
Because of the problems associated with the oral and injection routes of administration, physicians have sought other delivery mechanisms for achieving the desired cardiovascular or renal vascular action. Accordingly, transdermal and transmucosal (including buccal, lingual and sublingual) delivery routes have been explored. Those approaches are more pleasant than intramuscular delivery systems and are more reliable since they are less susceptible to gastrointestinal variability. These alternative medicament administration routes also result in more stable plasma and tissue concentrations of the medicament as it is absorbed by the body.
However, the transdermal and transmucosal delivery routes do not enable precise dose-to-effect compatibility (that is, administering a proper dose until the desire effect is achieved and doing so in a manner that eliminates the variabilities between patients). Moreover, these delivery systems do not easily enable rapid adjustment of plasma or tissue concentrations if clinical conditions dictate that a higher or a lower concentration would be more desirable in the next few minutes.
This is most easily seen with sublingual nitroglycerin tablets used for angina. When a patient has angina, the patient places a nitroglycerin tablet under his tongue (the "sublingual" administration route). From a practical standpoint, it is not possible to remove a sublingual nitroglycerin tablet once it has been placed under the tongue. The tablet is very small (typically, two to three millimeters in diameter) and dissolves very quickly.
In addition, because the tablet dissolves so rapidly, there is a lag time between the time the dose is given (i.e., when the tablet dissolves) and when the effects are observed. So, once it is under the tongue, the patient is more or less committed to taking the entire dose of nitroglycerin contained in the tablet, even if the angina would have been alleviated with only one-half of the dose in a tablet.
Consumption of the remainder of the tablet often results in an overdose and a severe headache. If the first tablet is not effective in treating angina, the patient must then take a second or a third table. This is a slow process and still may ultimately result in a relative overdose after the final tablet.
There are other practical problems with the sublingual administration route for nitroglycerin. Sublingual nitroglycerin tablets are intentionally very small in size so that they may be conveniently placed and maintained under the patient's tongue without evoking an undesirable response. However, the small size of the tablet makes them difficult for the patient to handle.
Another approach to overcoming the problems associated with the injection and oral delivery routes has been to incorporate the cardiovascular-acting renal vascular-acting drug into a nasal spray. However, since intermittent, multiple sprays of the drug are required, patients find it difficult to deliver the appropriate dosage to alleviate their symptoms and avoid the problems and side effects of overdosing.
Moreover, the propellant in the spray can interfere with the effectiveness and accurate delivery of the proper dosage of the drug. Problems with the temperature stability of the ingredients and the angle of the sprayer can also affect the dose or drug actually delivered. While these nasal sprays have avoided some of the problems of the oral and injection routes, they have not solved many of the problems associated with the delivery of the precise dose necessary to relieve the symptoms of the patient while accounting for the patient's individual susceptibility to the cardiovascular-acting or renal vascular-acting drug.
For example, sprays incorporating nitroglycerin have been developed in which the drug is sprayed on the oral mucosa using a lingual aerosol canister (the "lingual" administration route). The nitroglycerin lingual aerosol spray delivers nitroglycerin in 0.4 mg metered doses. this in essence is a delivery of a series of 0.4 mg boluses of nitroglycerin, only providing an alternative method of delivery, without any improvement whatsoever in titratability. The dosage options are the same as tablets, i.e., increments of 0.4 mg doses. The dose is preferably sprayed onto or under the tongue and then the mouth is immediately closed. The spray canister delivers a fixed dosage for each spray. As in sublingual administration, lingual administration is relatively fast-acting, but if relief is not attained after the initial spray, additional sprays must be given. Again, this is a slow process which usually results in a relative overdose after the final spray. Moreover, the lingual spray suffers from the same problems as discussed above with respect to the nasal sprays.
Additionally, care must be taken to not shake the aerosol canister prior to use, since shaking may generate bubbles within the canister which impair the proper release of nitroglycerin from the device. Also, the spray should not be inhaled, and swallowing immediately after spraying should be avoided. For many patients, particularly geriatric patients, these administration techniques may be too complex.
Physicians may also recommend buccal administration of nitroglycerin or other cardiovascular-acting or renal vascular-acting drugs. Buccal nitroglycerin tablets are typically placed between the upper lip and teeth. The tablet surface develops a gel-like coating that adheres to the mucosal surface of the mouth. As long as the tablet remains intact, nitroglycerin continues to pass from the tablet matrix to the mucosal tissue where it is rapidly absorbed. If the tablet is chewed and broken up, an undesirable mount of nitroglycerin is released for submucosal absorption or, if swallowed, the nitroglycerin would be metabolized by the liver as discussed above. Since the nitroglycerin in a buccal tablet can enter the body in three different areas, depending upon whether the tablet remains in place or is chewed, it is often difficult to ensure that the proper dose is delivery.
When used properly, buccal nitroglycerin acts rapidly after placement in the mouth--almost as fast as sublingual nitroglycerin. Nitroglycerin is released into the buccal cavity so long as the tablet remains intact. The average tablet dissolution time is between three to five hours; therefore, many patients, particularly geriatric patients, will have difficulty keeping the tablet in place for so long. Tablet dissolution time and the effective amount of the medicament delivered to the patient varies from patient to patient, and even in a given patient, because of differences in saliva production, tongue manipulation, inadvertant chewing (displacement of the gel "seal"), and eating or drinking by the patient.
Because of the wide variation of dissolution times from patient to patient, the same buccal nitroglycerin tablet is likely to result in either an overdose or underdose, depending on the patient. Although it is theoretically possible to manually remove the buccal tablet from the mouth and later replace it so as to control the amount of nitroglycerin released to the patient, such a procedure is not very practical.
For instance, if the tablet is manually removed from the mouth by the patient, it is likely to become contaminated by the patient's touch. Further, many patients who need nitroglycerin medication are older; these patients have difficulty coordinating small tablets in their mouth and find it extremely difficult to handle the small tablets with their hands.
Another alternative method of administering cardiovascular-acting or renal vascular-acting drugs is by applying ointment or patches to the skin which contain the drug. For example, nitroglycerin will readily pass through the skin (the "transdermal" administration route) and into the patient's bloodstream. When ointment is applied to the skin, its effect is observed within sixty minutes, with a duration from four to eight hours. Nitroglycerin patches are designed to provide continuous treatment for up to 24 hours.
The effect of nitroglycerin ointment varies from patient to patient. The area of application of the dose as well as the site, dosage, state of hydration of the skin surface, and permeability are all variables affecting the patient's response. In addition, nitroglycerin ointment is impractical for many patients because of the difficulty in application, its mess, cosmetic problems, and potential staining.
A major advance in cutaneous administration of nitroglycerin occurred with the development of a sustained-release patch. These preparations contain nitroglycerin in a reservoir or matrix and are designed to provide constant delivery of the drug into the circulation for twenty-four hours. The rate of the drug release is primarily determined by the device itself, rather than the characteristics of the patient's skin. However, important questions regarding dosage requirements, efficacy, and duration of action remain unanswered. Several recent reports involving patients with either angina pectoris or congestive heart failure have questioned the efficacy of these products. Several mechanisms have been proposed to account for the variability of patient response. The development of tolerance, low nitroglycerin plasma levels and tissue concentrations secondary to poor absorption of the drug, and inability of the delivery system to deliver drug for a full twenty-four hours are all proposed explanations of this phenomenon.
Similarly, patients using nitroglycerin transdermal patches may have reasonable plasma and tissue concentrations of nitroglycerin, but they cannot easily or rapidly increase or decrease those concentrations except by pulling off the patches or adding additional patches. Both of the latter processes are, at best, gross adjustments because of the slow response in transdermal patches, which results in relative overdoes or underdose of nitroglycerin.
In addition to the problem of slow onset, recent research indicates that continuous use of transdermal patches results in the development of a tolerance to the nitroglycerin. This suggests that continued use of nitroglycerin transdermal patches may not be a practical alternative for many patients.
In view of the foregoing, it will be appreciated that it would be an important advancement in the art of administering cardiovascular, renal vascular and related drugs if suitable methods and compositions could be provided that were capable of rapid action, of avoiding the disadvantage of immediate metabolism through the patient's liver, and of not involving an injection.
Given the life-sustaining importance of the cardiovascular and renal vascular systems, any drug which affects these systems is potentially life threatening if administered improperly. It would be, therefore, a further advancement in the art of administering potent cardiovascular and renal vascular drugs if suitable methods and compositions could be provided that enabled individual patent fine-tuning of ideal doses (providing a dose-to-effect administration modality) so that doses could be adjusted not only on an individual basis but easily increased or decreased at each time of administration.
It would also be an important advancement in the art if methods and compositions could be provided that would give a physician, as well as the patient (in appropriate circumstances), control over the administration of medication so that a desired effect is not only obtained but also maintained during times when his cardiac status or blood pressure changed.
Such methods and compositions are disclosed and claimed herein.